Mechanisms of mRNA localisation and cytoskeletal transport

For cells to perform their elaborate functions, various components must be delivered to the right place at the right time. This is dependent on the cellular equivalent of a railway system; tiny machines called “molecular motors” transport “cargoes” to their destination by traversing a network of tracks within the cell. However, it is not clear how these motors recognise different cargoes and how these cargoes are sorted to different destinations. This is not only a fundamental problem in cell biology but is also relevant to the understanding and treatment of diseases; aberrant transport processes are associated with neurodegenerative illnesses and motors are frequently exploited by viruses and bacteria during infection.
We are studying the detailed mechanisms of motor-based transport in a genetically tractable model organism, the fruit fly Drosophila. In particular we have focused on how molecules of mRNA, which code for the proteins within cells, are trafficked to different destinations. By using advanced microscopy to visualise mRNA transport in living cells and reconstituted on glass slides, we can address the precise functions of specific proteins in motor transport. We also work directly on the roles of motors in neurons so we can begin to understand what goes wrong in several neuronal diseases.

Cytoplasmic transport of organelles and macromolecules by molecular motors is of fundamental importance for the establishment and maintenance of cell polarity. In addition, defective motor transport is implicated in neurological diseases and pathogenic viruses and bacteria frequently exploit cellular transport routes. The challenge of studying microtubule-based transport is that movements are driven by large macromolecular assemblies, with a single cargo often bound simultaneously by multiple opposite polarity dynein and kinesin motors.
Using a tractable model system in Drosophila embryos we have shed light on mechanisms responsible for polarised sorting of specific mRNA molecules by microtubule motors. We have revealed molecular links between localising mRNAs and dynein and used novel in vitro motility assays to show that long distance movement of the motor is activated by mRNA localisation signals. Recently, together with Andrew Carter’s lab at the LMB, we have used purified mammalian proteins to show that the adaptor protein BicD is a key factor in switching on dynein processivity. We have also elucidated the mechanisms of dynein regulation by Lissencephaly-1 and mRNA localisation signals.
We have also been investigating how cargo transport is orchestrated in neurons using the intact Drosophila nervous system as a model. We recently established a novel imaging assay in the adult wing and are using it to study the relationship between axonal transport and the healthy lifespan of neurons. We have developed and distributed optimised tools for CRISPR genome engineering in Drosophila, and are using these in several of our own projects.
Our long-term plans are to combine genetics, cell biology, structural studies and single molecule assays to understand the key processes that control sorting of cargos and pathogens by motors. This should have therapeutic relevance; for example, it may be possible to target drugs to discrete regions of the cell to maximise their efficacy or to develop agents that stimulate motor activity in order to alleviate problems associated with defective transport in neurodegenerative diseases.